Natural and Traditional Cures for Prostatitis

The 21 Day Prostate Fix

By Efrain Mudd on Tue, 23 Oct 2018

21 Day Prostate Fix written by Radu Belasco is a healthier alternative to drugs and invasive medical procedures. Radu Belasco is an early prostate problem sufferer, with a family history of prostate pain, problems and cancer. Using a unique system of natural remedies, he fixed his prostate problems and wrote them in his smash hit eBook The 21 Day Prostate Fix. It is about miraculous herbs and fruits from all over the world. These unique foods have the power to cure your prostates inflammation in record time and shrink it to a healthier size. Also, you will learn how to concoct the miracle elixir that will not just cleanse your prostate, but also burn body fat. Aside from these, youll get topnotch information on nutrition, so you can keep your prostate healthy and your sex drive at its peak. Plus, youll learn other health conditions that might be contributing to your prostate issues, so you can also remedy them and get your body in its best shape ever.

The 21 Day Prostate Fix Summary

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Prostate cancer is the most frequently diagnosed malignancy and second leading cause of cancer death in men in Western countries. Little is understood about its causes, but steroid hormones, particularly androgens, are suspected to play a major role. Human populations at high risk for prostate cancer may have slightly higher androgen production, circulating androgens, 5a-reductase activity, or androgen receptor transactivation activity than low-risk populations. Elevated circulating estrogens have been found in some high risk populations, such as African American men, suggesting estrogen involvement. Studies in rats have clearly demonstrated that testosterone is a weak complete carcinogen and a strong tumor promotor for the prostate, but the exact mechanisms of these activities are not clear. Treatment of rats with a combination of testosterone and 17 -estradiol can induce prostate cancer at high incidence, while androgens alone cause a low prostate cancer incidence, indicating...

With the exception of dogs and humans, spontaneously occurring prostate cancer is rare in most species 5-7,190 . It not understood why prostate cancer is so common in men whereas it is very rare in almost all other species. As indicated earlier, there are compelling reasons to implicate hormones, particularly androgenic and estrogenic steroids, in human prostate carcinogenesis. As will be demonstrated in the following sections, the same steroid hormones are also very powerful factors in the induction of prostate cancer in rodent species in which spontaneous prostate cancer is rare 17,56,191 . However, it is important first to point out that the various lobes of the rat prostate differ in their propensity to develop prostate carcinomas, either spontaneously or induced by carcinogens or hormones 17,190,191 . The rodent prostate, unlike the human or canine prostate, consists of distinct paired lobes - the ventral, dorsal, lateral, and anterior lobes the dorsal and lateral lobes are often...

Long-term administration of testosterone to rats markedly enhances prostatic carcinogenesis following initial treatment with chemical carcinogens that target the prostate because of tissue-specific metabolism (DMAB and BOP) and or concurrent hormonal stimulation of prostatic cell proliferation 69,70,191,196 -200,202,203,226 . The presence and magnitude of this enhancement appears to depend on several factors 190,191,197 . For example, after a single inj ection of BOP or MNU given to F344 rats without concurrent stimulation of prostatic cell proliferation, long-term testosterone treatment did not enhance prostatic carcinogenesis 200 . High incidences (66-83 ) of adenocarcinomas of the dorsolateral and or anterior prostate were induced by chronic treatment with testosterone following a single administration of MNU or BOP given during stimulation of prostatic cell proliferation in Wistar rats, or during and after ten repeated biweekly injections of DMAB in F344 rats 69,...

Cadmium can be carcinogenic for the rat ventral prostate as demonstrated by Waalkes and co-workers 227, 228 . The selective sensitivity of the ventral prostate lobe for the carcinogenic action of cadmium is most likely due to the lack of cadmium-binding proteins in this lobe 229 . A single injection of cadmium chloride produced early stage carcinomas in the ventral lobe, but only when cadmium-induced testicular toxicity was avoided, either by keeping the cadmium dose low or by antagonizing the testicular toxicity of cadmium by simultaneous administration of zinc. These observations indicate that cadmium induces proliferative lesions in the rat ventral prostate only when testicular function, conceivably testosterone production, is intact. In addition, these data suggest that androgens also act as tumor promotors in this system, but this hypothesis has not been tested. Other mechanisms may also be involved, because, for example, testosterone considerably increases disposition and...

As stipulated earlier, there are compelling reasons to assume that androgens play a critical role in prostate carcinogenesis, and there is experimental evidence to suggest that estrogens are involved as well 55 . Because of the hormonal nature of these steroids, receptor mediation has been proposed as the major mechanism by which androgens and estrogens act in the causation of prostate cancer 235 . For estrogens, however, non-receptor-mediated genotoxic effects are conceivable, in addition to receptor-mediated processes 55 . For an-drogens, mechanisms other than those mediated by androgen receptors seem unlikely, except for the generation of estrogens via aromatization. These potential mechanisms are discussed in the following sections. Prostatic mesenchyme is known to be a mediator of androgen action in the developing and adult rodent prostate and possibly the human prostate 236, 237 . Therefore, interactions between epithelial and stromal cells in the normal prostate are undoubtedly...

The prostate secretes a range of proteins related to its function, including proteolytic enzymes, acid phosphatase (ACPP), and prostate-specific antigen (PSA). In prostate tumors, some of these proteins are known to increase or decrease in the amount secreted. To test the application of secretory vesicle isolation to frozen human surgical specimens, samples were obtained from patients with prostate cancer, with institutional review body (IRB) approval and patient consent. Tumor and normal tissue were separated as described 47 and the content of the secretory apparatus was isolated. Proteins were digested with trypsin and analyzed by LC-MS in order to compare expression between each normal and tumor pair from all six patients. Significantly differentially expressed peptides were identified. Four of the best known prostate cancer-associated secreted proteins were found to be up-regulated, as expected, in the tumors. PSA, ACPP, kallekrin 2 (KLK2), and macrophage migration inhibitory...

Results from the earlier summarized rodent experiments clearly indicate carcinogenic and strong tumor promoting properties of androgens, and the results of a limited number of epidemiological studies provide some support for the concept that androgens may have such effects in humans. The mechanisms of the carcinogenic and tumor-promoting effects of androgens on the rodent prostate are not known with certainty. The very steep relationship between testosterone dose and prostate carcinoma response in rat models suggests involvement of an androgen receptor-mediated mechanism 199 . However, other mechanisms may also be involved. For example, Ripple et al. 239 observed increased oxidative stress in androgen-sensitive LNCaP human prostate cancer cells exposed to DHT, but it is possible that these effects were androgen receptor-mediated.

As summarized earlier, the results of epidemiological studies provide limited evidence for an association between prostate cancer risk and circulating levels of estrogens, which appear to be higher in African American men (under 50 years of age) than in European American men. This observation suggests that estrogens may be involved in prostate carcinogenesis, because men of African descent living in an American environment have the highest risk for prostate cancer world-wide. However, most direct evidence in support for a role of estrogens in prostate carcinogenesis is derived from studies with treatment of NBL rats with testosterone and 17 -estradiol 206,207,244 . The mechanisms involved in the prostatic effects in this model are a mixture of estrogen receptor-mediated and non-receptor processes. In addition, there is evidence to suggest that the mechanisms involved in hormonal induction of rat prostate carcinomas, which originate from the periurethral prostatic ducts, are different...

Neuroendocrine molecules play a significant role in the progression of human prostate cancer (PCa) and its neuroendocrine differentiation has been associated to a worse prognosis. Evidence exists that, among these molecules, the pleiotropic neuropeptide Y (NPY) and the related receptors may play a role in the normal prostate as well as in the progression of human PCa, which represents one of the most common malignant diseases among men in the Western world. The role of NPY in PCa biology appears to vary in different in vitro human PCa cell systems, since it has been found to reduce the proliferation of LNCaP and DU145 cells, but to stimulate the growth of PC3 cells. These effects are mediated mainly by the NPY Y1 receptor and are associated with a clone-specific pattern of intracellular signaling activation, including a peculiar time-course of MAPK ERK1 2 phosphorylation (long-lasting in DU145 and transient in PC3 cells). In conclusion, several studies support the concept...

Worldwide prevalence of prostate pain is said to be 2-10 1 however, other pelvic pains may be included in this figure as diagnosis may be difficult. In a postal survey of 3000 Canadian men the majority of sufferers were aged 20-49 or over 70 2 , with 50 of men given the diagnosis of prostatitis symptoms at some point during their lives 3 . In the USA 8 of urology clinic patients and 1 of patients in general clinics are given the diagnosis of prostatitis 4 . Nickel and his group reviewed the National Institutes of Health (NIH) chronic prostatitis symptom index data 5 . This represents a cross-sectional postal survey of 2987 men aged 20-74 years in Canada (response rate of 29 ). It identified 9.7 of subjects as having chronic prostatitis-like symptoms according to the NIH chronic prostatitis symptom index. In this group the average age of the prostati-tis population was 50 years and the prevalence was 11.5 in men younger than 50, and 8.5 in the older men. The relatively low response...

The first clinical evidence for the utility of an a-adrenoceptor antagonist in the symptomatic treatment of benign prostatic hyperplasia (BPH) was provided by Caine and colleagues (52) using phenoxybenzamine, an irreversible antagonist that alkylates both a1- and a2-adrenoceptor adrenoceptors. The efficacy of phenoxybenzamine has been confirmed in several subsequent studies (53,54), and the intravenous administration of a nonselective a-adrenoceptor antagonist, phentolamine, was shown to relieve the

Prostate cancer is one of the most common neoplasia in men. This cancer is clinically and genetically heterogeneous and varies in his biological aggressiveness. We performed gene expression profiling on 93 human prostate samples including 17 normal biopsies, 67 clinically localized adenocarcinomas of the peripheral zone of the gland and 9 benign prostatic hyperplasia (BPH). Comparative hybridization of tissues against a commercially available normal prostate reference was realized using oligonucleotide glass arrays with sequences representing over 18,000 well-characterized human genes, in a dye-swap duplication scheme. The aims of the study were to identify genes involved in carcinogenesis to improve the histological classification with molecular data to discover diagnostic and prognostic biomarkers to detect and or anticipate the clinical evolution of the cancer by correlating gene expression profiles with follow-up data. We also focused on a family of transcription factors whose...

Chronic prostatitis chronic pelvic pain syndrome (CP CPPS) is defined as pain attributed to the prostate in the absence of identifiable pathology and has often been referred to as prostatodynia. Hallmark features consist of persistent complaints of urinary urgency, dysuria, poor urinary flow, and perineal discomfort without evidence of bacteria or white blood cells in prostatic fluids. It serves as a male-specific corollary to interstitial cystitis in that it has similar symptomatology, is a diagnosis of exclusion, and has a presumed site of pain generation. Infectious, inflammatory, neurological, and referred gastro-enterological etiologies of the pain need to be ruled out. Cystoscopic findings of interstitial cystitis have been found in males with the diagnosis of prostatodynia.61 Wesselmann et al.98 have suggested that interstitial cystitis, CP CPPS (male), and vulvodynia (female) may all be variations of a generalized disorder of the epithelium of the urogenital sinus. To further...

Prostate cancer develops from the glandular epithelium of the small organ which secretes most of the seminal fluid in males. Most prostate cancers can be clearly identified as adenocarcinomas (Figure 19.1). The prostate is about as big as a Figure 19.1 Histology of prostate adenocarcinoma The star marks a normal glandular tubule with clearly distinguishable basal and secretory layers. The arrow points to the carcinoma area with dysmorphic glandular tubules. Figure 19.1 Histology of prostate adenocarcinoma The star marks a normal glandular tubule with clearly distinguishable basal and secretory layers. The arrow points to the carcinoma area with dysmorphic glandular tubules. chestnut in younger males and almost regularly increases in size after mid-life, mostly by expansion of the mesenchymal stroma. This leads to a benign tumor, 'benign prostate hyperplasia' (BPH). BPH is rarely life-threatening, but by compressing the urethra which passes through the prostate, it can lead to more or...

The prostate gland produces part of the seminal fluid. Almost all prostate cancers arise from the glandular epithelium, which consists of a basal and a secretory layer. In the normal gland, basal cells constitute the proliferative fraction. They give rise to intermediate cells which terminally differentiate into secretory cells that line the ducts and produce prostate-specific proteins such as PSA. They turn over slowly and are continuously replaced (Figure 19.5). Figure 19.5 Organization of cell proliferation and differentiation in the normal prostate This hypothetical scheme is accepted in general, although its details are debated A subset of basal cells is thought to represent progenitors for differentiated cells of the luminal layer by way of intermediate cells. It is not certain to which extent they possess further stem cell properties, in particular, whether they give rise to specialized cells in the basal layer, e.g. neuroendocrine cells. Many cells in the basal layer display...

Some of the tumor suppressors and oncogenes that are so crucially involved in other common cancers, TP53, PTEN, MYC, EGFR, and BCL2, contribute also to the progression of prostate cancer towards androgen-independent growth and metastasis. However, they do not appear to be responsible for the initial development of this carcinoma. Likewise, mutations or polymorphisms in these genes certainly do not account for the 4-fold increased risk of first-grade relatives of prostate cancer patients to develop the same disease. In other major cancers, studies of inherited cancer syndromes have helped to identify key genes involved. In prostate cancer, this approach is complicated by several factors. (1) There are very few cases of prostate cancer at a conspicuously early age. Rather, an exponential increase sets in around the age of 50 (Figure 19.2). Specifically, there is no hereditary syndrome with an obvious predisposition towards prostate cancer. (2) With a cancer that appears late in life, it...

In normal prostate tissue, proliferation and survival of epithelial cells are controlled by growth factors and matrix proteins supplied by the mesenchymal cells which surround the glands as well as on nutrients and oxygen supplied via blood vessels in the mesenchyme. The tissue structure of the prostate, like that of other organs, is dependent on mutual interactions between epithelial and stromal cells ( -8.6). As prostate cancers progress, these relationships change, most dramatically in metastases. In general, tumor progression is associated with increased growth autonomy. In some cancers, this growth autonomy is established by mutations in cell cycle regulators ( 6.4) or by inappropriate activation of cancer pathways that control the cell cycle ( 6). In many cancers, including prostate cancers, autocrine growth factor loops contribute to growth autonomy. To various extents, however, all cancers remain dependent on interactions with stroma, and this relationship is particularly...

Although the antiandrogenic treatment of metastatic prostate carcinoma is palliative, life expectancy is increased and thousands of patients have benefited. When distant metastases already are present, hormonal therapy becomes the primary treatment for prostate cancer. Pharmacological approaches to reduce the concentrations of endogenous androgens or inhibit their action include antiandrogens, or more commonly, the administration of gonadotropin-releasing hormone (GnRH) agonists or antagonists with or without antiandrogens (see below). Among men with metastatic prostate cancer, &gt 90 have an initial favorable response to primary hormonal therapy with androgen deprivation therapy (ADT). This is manifest as disease regression or stabilization and relief of cancer-related symptoms. The average time to progression is 18-36 months, making ADT one of the longest-lasting beneficial treatments in any advanced solid tumor. There is a survival benefit to ADT. Disease progression after ADT...

Ahluwalia et al. 139 studied African Americans and black Nigerian men that were matched controls in a case control study of prostate cancer. Plasma levels of testosterone and estrone were significantly higher in the Americans than in the Nigerian men, whereas levels of DHT and 17 -estradiol were not different. Similar differences were found for the prostate cancer cases. Hill et al. 62-64 compared the hormonal status of small groups of middle-aged African American, European American, and black (rural) South African men consuming their customary diets. In a separate study, African American, European American, and black South African boys and young African American and Ross et al. 133 compared healthy young African-American men and young US Caucasian males. Total circulating testosterone and free testosterone were 20 higher in the black men than in the white group. Serum estrone concentrations were also higher (by 16 ) in the blacks than in the whites. There were no differences between...

Etiologic factors that initiate and enhance the progression of prostate malignancy are beginning to emerge. One major research focus is the role of diet and nutrition. Dietary factors possibly linked to prostate cancer are numerous however, the most provocative data focus attention upon those nutrients and phytochemicals involved in oxidative defense. A clear understanding of how anti-oxidants may protect the prostate from the genetic damage that is associated with tumor development remains unclear. It is well established that the consumption of fruit and vegetables is associated with reduced risk of many cancers.133,134 These strong and reproducible epidemiological associations have led to an interest in determining the specific components within whole foods responsible for this observed reduced risk. However, supplementation with certain anti-oxidant compounds has not been successful. The anti-oxidant -carotene which when provided as a dietary supplement to populations at high risk...

Prostate cancer incidence and mortality rates have increased in the US over the few decades preceding the frequent use of prostate specific antigen (PSA) for early detection 10 . Incidence rates have increased substantially since the mid-1980s because of use of PSA screening for early detection 1 ,but rates have recently begun to decline 11 . In 1999,179,300 new cases of prostate cancer are expected and 37,000 deaths from this malignancy 12 . The epidemiology of prostatic cancer has been reviewed in depth elsewhere 10,13-17 . The most important potential risk factors are summarized below, with special attention to those possibly related to hormonal factors.

The symptoms of BPH (e.g., urethral obstruction leading to weak stream, urinary frequency, and nocturia) result from mechanical pressure on the urethra (due to an increase in smooth muscle mass) and an a-mediated increase in smooth muscle tone in the prostate and neck of the bladder. a1 receptors in the trigone muscle of the bladder and urethra contribute to the resistance to outflow of urine prazosin reduces this. The efficacy and importance of a receptor antagonists in the medical treatment of BPH have been demonstrated in multiple controlled clinical trials. Finasteride (propecia) and dutasteride (avodart), which inhibit conversion of testosterone to dihy-drotestosterone (see Chapter 58), can reduce prostate volume in some patients however, their overall efficacy appears less than that of a1 receptor antagonists. Selective a1 receptor antagonists have efficacy in BPH owing to relaxation of smooth muscle in the bladder neck, prostate capsule, and prostatic urethra. Recent studies...

Prostate cancer is the most common hormone-related cancer in men and the incidence in the United Kingdom (UK) has been rising rapidly by about 3-4 per year 92 . High-fat and high-meat diets are currently linked to increased risk of the disease, and like breast cancer, it is comparatively rare in Far Eastern populations consuming soybean. The incidence of and mortality from prostate cancer is very much lower in Asian men in comparison to men from the West 121 . In addition, men who adopt a vegetarian diet are also at lower risk from prostate cancer 122 . The diets of Asian and vegetarian men are not only much lower in fat than the traditional diet of omnivorous Western man, but they are also a rich source of weak dietary estrogens 13 . It has been estimated that the traditionally-eating Chinese man consumes, on average, 35 times more soy than the North American man 56 . Lifetime exposure to the isoflavonoids in soy may play a significant role in the low incidence of prostate cancer in...

The level of physical activity may be a possible risk factor for prostate cancer, but the evidence for such an association is inconclusive at present 17,61,115 . Exercise may influence androgen concentrations 116,117 , and thus it is possible that the type and extent of physical activity influence circulating androgen concentrations and, thereby, possibly prostate cancer risk. The evidence that obesity or an increased body mass index is a prostate cancer risk factor is contradictory at present (see 17, 61,118 ), but an increase in prostate cancer risk with increasing upper arm circumference and upper arm muscle area, but not fat area, has been observed 119 . This positive association between prostate cancer risk and muscle mass, but not fat mass, suggests exposure to endogenous or exogenous androgenic hormones or other anabolic factors 119,120 . There are reports that body mass index is inversely correlated with plasma testosterone and SHBG levels and positively correlated with 17...

As mentioned earlier, a causal relation between androgens and prostate cancer development is biologically plausible. Prostate cancer develops in an androgen-dependent epithelium and these cancers are androgen-sensitive and respond to hormonal therapy by temporary remission followed by relapse to a hormone-refractory state. There are also case reports of prostate cancer in men that used androgenic steroids either as anabolic agents or for medical purposes 123128 . The endocrine status of prostate cancer patients has been compared with that of control subjects, but these studies have not provided a consistent pattern 129-132 and are probably not very meaningful, because the presence of the cancer may by itself alter hormonal status, and they are not likely to be informative about the endocrine status prior to the onset of the disease 13,17,123 . More meaningful are nested case-control studies in ongoing cohorts and studies comparing healthy males in populations that are at high risk for...

Nomura et al. 159 compared prostate cancer cases with matched controls from a cohort of Hawaiian Japanese men followed for approximately 14 years. There were no significant differences between cases and controls or associations with risk for circulating testosterone, DHT, estrone, 17 -estradiol, and SHBG measured once at the start of the cohort study. There was a relation between risk and an increasing ratio of testosterone to DHT, which was borderline significant (0.05&lt p&lt 0.1). The results from this nested case-control study may suggest an inverse relation between (peripheral) 5a-reductase activity and prostate cancer risk. Barrett-Connor et al. 160 followed a cohort of white upper-middle class Californian men for a period of 14 years. There was no significant relation between risk for prostate cancer and base-line serum concentrations of testosterone, estrone, and SHBG. However, relative risk increased linearly with increasing serum level of androstenedione, a testosterone...

The results of the studies summarized above do not provide unequivocal or strong evidence for any particular association between prostate cancer risk and hormone exposure (circulating levels of hormones) or polymorphisms in genes that encode for proteins involved in steroid hormone action or metabolism. The only associations with prostate cancer risk that have been observed consistently in at least three studies are slightly higher circulating testosterone and estrogen levels in high risk African American men as compared with lower risk European American men and a functional polymorphism in the androgen receptor gene however, these associations are weak at best and mostly not statistically significant. There are no epidemiologic data about prostate cancer risk and exposure to exogenous hormones, including environmental agents with hormonal activity. the interrelationships between various hormones 143, 163 which are taken into account in very few studies during data analysis 164 ....

There are only few clearly established and strong risk factors for prostate cancer which are consistently observed in epidemiologic studies (1) African-American descent, (2) a Western life style, in particular Western dietary habits, and (3) a family history of prostate cancer. Less consistently found and weaker risk factors are a history of venereal disease, and employment in farming, the armed services, and the nuclear industry. Elevation of bioavailable and bioactive androgens in the circulation and in the prostatic target tissue may be an important and biologically very plausible risk factor. As will be detailed later, the results of several animal model studies strongly support this contention, but more research is needed to confirm and further define this association in humans, and to establish its underlying biological mechanisms (increased androgen production or 5a-reductase activity and decreased DHT catabolism) (see also 173 ). Since circulating testosterone levels may be...

Noble first demonstrated that testosterone is carcinogenic for the rat prostate, and he established that sequential treatment with testosterone and estrogens was even more effective than testosterone per se. Noble used the Noble (or NBL) rat strain which he developed 194 . Long-term treatment of NBL rats with a combination of testosterone and 17 -estradiol leads to a high incidence of adenocarcinomas, that develop from the periurethral ducts of the dorsolateral and anterior prostate 205-207 . The development of these tumors is preceded by the appearance of epithelial dysplasia in these ducts and in the acini of the dor-solateral prostate 206-208 . Carcinomas developing from the acinar dysplasia in the periphery of the prostate gland have not been reported, and the malignant potential of these lesions, which are morphologically similar to human prostatic intraepithelial neoplasia (PIN), is not certain 206,207 . Treatment of NBL rats with diethylstilbestrol (DES) combined with...

Carcinogenic effects on the male accessory sex glands have been reported after perinatal exposure of mice, rats, and hamsters to DES (see 17, 209-211 ). McLachlan and co-workers 209,212 found that 25 of the male offspring of CD-1 mice that had been treated with DES on days 9-16 of gestation had nodular enlargements of the coagulating gland, ampullary glands, and colliculus seminalis at an age of 9-10 months. One animal had a lesion in the area of the coagulating gland and colliculus seminalis that resembled early cancer 212 .Of eight prenatally DES-exposed male mice that survived for 20-26 months, one had an adenocarcinoma of the coagulating gland, three had hyperplasia of the coagulating gland, two had hyperplasia of the ventral prostate, one had a carcinoma of the seminal vesicle, and two had squamous metaplasia of the seminal vesicle,but no such lesions occurred in control animals 209,210 . Prenatal DES exposure of mice also induced testicular tumors (particularly of the rete...

Androgen receptor-mediated stimulation of prostatic cell proliferation by androgens has been implicated in human prostate carcinogenesis 135, 235 . However, there is no direct evidence that elevation of circulating testosterone leads to increased cell proliferation in the human prostate. Androgen administration to castrated rodents causes elevation of prostatic cell proliferation similar to that observed in cell cycle synchronization experiments with cells in vitro 240 . The increase in prostatic cell proliferation caused by androgen administration to castrated rodents is only transient, and after a few days cell turnover returns to its normal very low level 240 . Thus, continued androgen treatment of rodents does not result in constantly elevated rates of cell proliferation in the male accessory sex glands, but probably only supports differentiation. DHT may even suppress prostatic cell proliferation in intact rats 206 . Thus, continuous stimulation of cell proliferation is unlikely...

Any hypothesis implicating androgens in prostate carcinogenesis has to consider androgen receptor function and androgen metabolism. Ross et al. 135 have developed the concept that genetically determined differences in androgen receptor activity as well as the activities of steroid biosynthetic enzymes, 5a-re-ductase, and enzymes that metabolize DHT are major determinants of risk both at the population and individual levels (see also 18 ). Functional polymorphisms in the genes that encode for these enzymes and the androgen receptor have been hypothesized to be at the core of this notion 18,135 . The earlier summarized and evaluated results of endocrinological studies and evidence for a role of these polymorphisms in human prostate carcinogenesis lead to the following conclusions to date there is little evidence that functional polymorphisms in the 5a-reductase gene and differences in 5a-reductase activity are important determinants of prostate cancer risk. However there is some...

The prostate contains estrogen receptors, and both the estrogen receptor-a and -b are present in the rat prostate 247 . Thus, involvement of direct receptor-mediated effects of estrogens in prostate carcinogenesis is plausible, but rodent studies using anti-estrogen treatments (such as tamoxifen and ICI-182,780) have yielded contradictory results. The prostate tumor-promoting effects of testosterone may involve estrogen generated by aromatization. However, simultaneous administration of testosterone and tamoxifen did not alter the prostate carcinogenesis enhancing effect of the androgen in experiments in rats injected with prostatic carcinogens prior to the hormone treatment 248 McCormick and Bosland, unpublished data . On the other hand, ICI-182,780 blocked the induction of epithelial dysplasia in the prostatic periphery in NBL rats treated with testosterone and 17b-estradiol 249 the effects of this antiestrogen on induction of periurethral prostate carcinomas are not known....

Estrogens are capable of producing DNA damage in the target tissues for estrogen carcinogenicity, independent of their interaction with the estrogen receptor 252 . Gladek and Liehr 253 have found a direct DES-DNA adduct in the kidney of male hamsters treated with DES, as well as indirect estrogen-generated DNA adducts (perhaps of endogenous origin and of undetermined structure) detectable by 32P-postlabeling 254 . Both observations are thought to be related with the formation of catechol estrogens that undergo redox cycling during which reactive intermediates and reactive oxygen species are generated and lipid peroxidation can be initiated 252 . In the NBL rat, treatment for 16 weeks with testosterone plus 17 -estradiol enhanced the formation of a chromato-graphically unique endogenous adduct selectively in the periurethral region of the rat dorsolateral prostate, which is the site of the carcinogenic effect of this treatment 255, Bosland, unpublished data . Ho and Roy 256 found...

Perinatal estrogen exposure of mice resulted in epithelial dysplasia of the peri-urethral proximal parts of the dorsolateral and anterior prostate and seminal vesicles 214,215 , as well as in carcinomas in these areas 212 , as summarized earlier. In addition, mice that were neonatally estrogenized hyper-responded to secondary estrogen treatment 214 . These very same tissue areas contain estrogen receptors which indicates their estrogen sensitivity 214 . However, the activity of 17 -estradiol hydroxysteroid oxidoreductase, believed to be a mar ker of estrogen sensitivity, and incorporation of tritiated thymidine in epithelial compartments of these tissues were not changed in response to secondary treatments with estrogen in neonatally estrogenized mice 214, 215 . In response to secondary androgen treatment, tritiated thymidine incorporation was markedly increased selectively only in the stromal cells of the anterior and ventral prostate, indicating a lasting effect of neonatal estrogen...

There are no known exogenous hormonal or non-hormonal exposures that are associated with prostate cancer risk, with the exception of exposure to a western life style (including a high fat diet), to an African American environment, and, perhaps, to venereal disease, unknown factors related to farming, and employment in armed services and the nuclear industry. None of these associations point to specific chemicals, hormones, or other factors. In view of the high frequency of this malignancy in Western countries, this lack of known specific risk factors is remarkable and may indicate that there are many exogenous risk factors for prostate cancer which are too ubiquitous and overlapping to be detectable by epidemiologists. It is also possible that there are strong endogenous determinants of prostate cancer risk which are overwhelming most exogenous risk factors in epidemiological analyses. Androgenic hormones and androgen receptor mechanisms are prime candidates to be such important...

Both clinical and epidemiological data suggest that dietary estrogens may have a beneficial effect on the human endocrine system. Breast cancer, prostate cancer, colon cancer, menopausal symptoms, heart disease, and osteoporosis share a common epidemiology in that they are rare in Far Eastern populations eating traditional diets containing soybean products compared with Western populations. However, with Westernization and loss of traditional eating patterns, the pattern of disease incidence is also changing in these countries. Cross-sectional studies have shown higher phytoestrogen levels in the urine and plasma of populations at lower risk of these diseases 28, 91 . This section will focus on the beneficial role which phytoestrogens may play in breast cancer, prostate cancer, colon cancer, endogenous hormones, the menstrual cycle, menopausal symptoms, cardiovascular disease, and osteoporosis.

Among treatment groups suggesting that the deficits in male sexual behavior were not due to deficits in adult gonadal function. These data provide evidence that lactational exposure to phytoestrogen diets can alter neuroendocrine development in both female and male rats. In addition, feeding flaxseed, the richest source of the mammalian lignan precursor secoisolariciresinol digly-coside, to rats during a hormone-sensitive period has demonstrated reproductive effects 270 . The female offspring had shortened anogenital distance, greater uterine and ovarian relative weights, earlier age and lighter body weight at puberty, lengthened estrous cycle, and persistent estrus, whereas the males had reduced postnatal weight gain and greater sex gland and prostate relative weights, suggesting estrogenic effects. These examples in animals suggest that the phytoestrogen content of soy products and other dietary products may induce unintended adverse effects on reproduction and development in...

Estrogens are formed from androgens by a widely distributed mono-oxygenase enzyme system called aromatase, containing NADPH-cytochrome c reductase and cytochrome P-450. Estradiol (i. e., 17 -estradiol, E2), by far the most potent endogenous estrogen, is synthesized from testosterone by aromatase present in the ovaries, placenta, and various other estrogen target tissues such as the brain, prostate, uterus, and mammary gland. In turn E2 can be metabolized to multiple hydroxylated products by enzymes of the P450 family, or broken down to sulfates, glucuronides, or fatty acid esters. The latter three pathways are also reversible, creating active estrogens 5,6 .

In this chapter we will address the following question to what extent does current evidence from reproductive biology and epidemiology support a causal role for endocrine disrupting chemicals (EDCs) in the pathogenesis of altered male reproductive function We have divided this discussion into two parts epidemiology, presented first, followed by the relevant reproductive biology. Our discussion will focus primarily on semen quality, testicular cancer, hypospadias, and cryptorchidism, which we will refer to collectively as adverse male endpoints. Other male reproductive parameters, including altered prostate development and prostate cancer, will also be discussed briefly. An historical overview of EDCs, beginning with the discovery of the first synthetic estrogen in 1933, is presented first. 2.2 Incidence of Testicular and Prostate Cancer 140 10 Development of the Prostate Example of Opposite Effects of High and Low Doses

Incidence of Testicular and Prostate Cancer As with testicular cancer, prostate cancer rates showed a steady increase from the 1960s through the mid-1980s. However, once the use of the prostate specific antigen (PSA) test became widespread in the mid-1980s, trend data became difficult to interpret. Prostate cancer rates are highest in Northern Europe and North America. Unlike testicular cancer, incidence and mortality in the United States are highest among African-Americans 52 . Why African-Americans show a markedly higher incidence of prostate cancer and a markedly lower incidence of testicular cancer relative to Caucasians remains unknown.

With respect to prostate cancer, there is no evidence that either birth order or maternal age is related to risk 85 . In relation to low birth weight and prematurity, the pattern for prostate cancer appears to be opposite to that seen for testicular cancer. Ekbom et al. 85 found no premature births among 80 cases, compared to 6 of 196 controls (p 0.02) although mean birth weight was higher, though not significantly, among cases. Ross and Henderson 86 suggest that the dramatic (approximately 30-fold) difference in risk of prostate cancer between African-American and Japanese and Chinese men may be due, in part, to differences in androgen secretion and metabolism. For example, higher testosterone levels have been found in maternal serum of African-Americans 78 , as well as in young adult males 87 .

There are a number of experimental studies in laboratory animals relating developmental exposure to EDCs to changes in testicular function in adulthood. For example, a single administration of a low dose (50 ng kg to 1 g kg of body weight) of dioxin to pregnant female rats on gestational day 15 resulted in altered sexual differentiation in male and female offspring 136 . The lowest dose of dioxin tested (50 ng kg body weight) resulted in a concentration in fetal organs of approximately 5 parts per trillion (5 pg g tissue). Since this dose is within the range of human exposure 137 , these results are environmentally relevant. A single administration of dioxin to pregnant female rats produced a decrease in circulating testosterone and in anogenital distance in male offspring at birth. Effects on adult sex behavior in male offspring included changes in mounting, intromitting, number of ejaculations and latency to ejaculation, as well as the exhibition of the female sexually receptive...

Kidney, and brain in males in the liver, kidney, genitals, and brain, an important effect of androgen is the imprinting of enzyme systems that markedly influence tissue function and, more generally, homeostasis, throughout the remainder of life 1 . Without the secretion of androgen by the fetal testes, the secondary sexual characteristics are those typical of females. However, there is also evidence that estrogen plays an important role in the normal processes of mas-culinization of the brain and accessory reproductive system 161,167,168 . As a result, EDCs that interfere with the normal activity of either androgen or estrogen can disrupt the processes mediating the differentiation of accessory reproductive organs in males these include the efferent ducts, epididymides, vas deferens, and seminal vesicles, which differentiate from the Wolffian (mesonephric) ducts under the local (not systemic) action of testosterone. In contrast, circulating testosterone mediates the differentiation of...

Naturally occurring variation in the levels of testosterone and estradiol in both male and female mouse, rat, and gerbil fetuses (due to being positioned in utero between male or between female fetuses) leads to marked differences in a wide range of reproductive traits morphology and functioning of internal and external genitals in males and females, and aggressive and sexual behavior in males and females 190-192 . The magnitude of the differences in hormone levels between male fetuses that develop in utero between two males (2M males) and male fetuses that develop between two females (2F males) in mice is significant. For example, on gestation day 18, one day after the initiation of prostate development, 2F males have significantly higher (101 pg ml) total serum estradiol relative to levels in 2M males (78 pg ml). 2F males average 0.2 pg ml free serum estradiol, while 2M males average 0.16 pg ml free serum estradiol. These findings suggest that a difference between 2M and 2F males in...

We focus here on the effects of estrogens on the prostate, since this is the most disease-prone organ in the human body. Prostatic buds form from the urogenital sinus just below the developing bladder. Buds begin forming from the urogenital sinus on gestation day 17 in mice and week 10 in humans at birth, the mouse is similar to a human fetus at approximately week 17 of gestation 191 . The prostatic glands empty into the portion of the urethra surrounded by the prostate. Urogenital sinus mesenchyme, which shows estrogen as well as androgen binding 192,211-213 , regulates differentiation of the prostatic duct ep ithelium during fetal and neonatal life in mice 191,214-217 . One mechanism through which estrogens affect epithelial cell differentiation in the prostate is through modulation of the action of androgen during prostate development. In a recent study of developmental effects of natural and synthetic estrogens 167 , evidence for an inverted-U dose response relationship in the...

Prostate Squamous cell cancer of dorsolateral prostate 268 Prostate Treatment of pregnant females with high doses of DES interferes with the action of Mullerian inhibiting hormone on Mullerian duct regression in male mice 128 and humans 229 . The utricular remnant within the prostate, which is of Mullerian origin, is enlarged and there is marked hyperplasia and metaplasia of prostatic ducts in the central zone of the adult prostate 229,230 . As mentioned above, exposure of the neonatal mouse to high doses of DES has been shown to interfere with normal development of the prostate 213, 231, 232 . Squamous metaplasia of prostatic and coagulating gland (dorsocranial prostate) ductal epithelium in male mice and rats has also been reported after exposure to exogenous estrogen or estrogenic chemicals during early life 128 . This endpoint is also characteristic of the effect of estrogen on rat prostatic cells in culture 200 . Exposure of rats and mice to high doses of DES during development...

Concerns have been raised regarding the reproductive and health hazards of chemicals in the environment that have potential endocrine disrupting effects. These concerns include increased incidences of breast, ovarian, and uterine cancer, endometriosis, fibroids, infertility, and early menopause in women in men, alterations in sex differentiation, decreased sperm concentrations, benign prostatic hyperplasia, prostatic cancer, testicular cancer, and reproductive problems have been suggested. Studies with the potent synthetic estrogen diethyl-stilbestrol (DES) have shown that exogenous estrogen exposure during critical stages of development results in permanent cellular and molecular alterations in the exposed organism. These alterations manifest themselves in the female and male as structural, functional, or long-term pathological changes including neoplasia. Although DES is a potent environmental estrogen, studying its effects at low dose levels in an experimental animal model offers a...

Permixon is an antiandrogenic extract of the saw palmetto that is used in some European countries to treat androgen-dependent prostatic diseases 53 . Clinical studies indicate that it is effective in this regard. Mechanistically, it has been reported to act as an AR antagonist 54 and to inhibit the activity of 5a-reductase activity, which metabolizes testosterone to dihydrotestosterone (DHT) 55 . Rhodes et al. 56 reported that permixon failed to inhibit testosterone- or DHT-stimulated prostate growth in castrated rats, suggesting that it was not antiandrogenic, while, in contrast, Paubert-Braquet et al. 57 reported that the lipidosterolic extract of Serenoa repens (permixon) inhibited the effects

When we administered vinclozolin by gavage to the dam at 0,3.125,6.25,12.5, 25,50, or 100 mg kg day from gestational day (GD) 14 to postnatal day 3 110 , doses of 3.125 mg kg day and above reduced AGD in newborn male offspring and increased the incidence of nipples areolas in infant male rats. These effects were associated with permanent alterations in other androgen-dependent tissues. Ventral prostate weight in one year old male offspring was reduced in all treatment groups (significant at 6.25,25,50, and 100 mg kg day) and permanent nipples were detected in males at 3.125 (1.4 ), 6.25 (3.6 ), 12.5 (3.9 ), 25 (8.5 ), 50 (91 ), and 100 (100 ) mg kg day. To date, permanent nipples in adult male offspring (not to be confused with areolas or what some authors incorrectly described as retained nipples in infant male rats) have never been observed in a control male from any study in our laboratory.Vinclozolin-treatment at 50 and 100 mg kg day induced reproductive tract malformations,...

To resolve this apparent discrepancy, we administered linuron by gavage in oil at 100 mg kg day from days 14-18 of gestation 115 . AGD in male offspring, adjusted by analysis of covariance for body weight, was reduced by about 30 (pup weight was down 20 ), and the incidence of areolas (with and without nipples) seen in the male offspring as infants was increased from 0 in controls to more than 44 in the linuron-treated males. Linuron treatment also induced epispadias in 1 13 males (partial hypospadias with the urethral opening half way down the phallus) and several androgen-dependent tissues were reduced in size in linuron-treated male rats, including the seminal vesicles, ventral prostate, levator ani bul-bocavernosus muscles, and epididymides. While the above effects are consistent with the action of a relatively weak AR antagonist, the high incidences of epididy-mal and testicular malformations (&gt 50 of the linuron-treated males displaying agenesis or atrophy of one or both...

In 1995 Kelce et al. 106 reported that p,p'-DDE displayed antiandrogenic activity both in vivo and in vitro that was similar to vinclozolin, both being AR antagonists. In vitro, p,p'-DDE binds to the AR and prevents DHT-induced transcriptional activation in cells transfected with the human AR and inhibits an-drogen-dependent gene expression in vivo 105 . Interestingly, Wakeling and Visek 134 reported that several chlorinated pesticides including dieldrin and o,p'-DDT inhibited binding of DHT to proteins in the rat prostate cytosol (they did not examine p,p -DDT or DDE).

The PCB congener 169 is an Ah receptor agonist with a toxic equivalency factor of about 0.001, as compared to the potency of TCDD. PCB 169 treatment during pregnancy (administered as a single dose of 1.8 mg kg to the dam on GD 8) alters reproductive development of LE hooded male and female rats in a manner almost identical to TCDD 115 . However, the sensitive androgen-dependent measures (AGD, areolas, and nipples) were not altered in treated males. Similar to TCDD treatment, PCB 169 treatment accelerated the age at eye opening and induced vaginal threads and mild hypospadias (urethral opening separate from the vaginal canal with cleft phallus) in female offspring, without reducing AGD or inducing areolas or nipples in males. In this regard, these organs were more affected in PCB 169-treated males at 65 days of age than in middle-aged males. PCB 169 treatment in utero increased the incidence of prostatitis in the dorsolateral lobe of the prostate of old male rats from 2 15 in controls...

Termed agonists if they bind the receptor and induce hormone action (for a comparative discussion of short-term assays for certain EDCs see 18 ). EDCs are antagonists if they bind the native receptor, yet block hormone action. Traditionally, investigators have used receptor-binding assays to measure relative binding affinity of a suspected EDC 19 . Here, a graded concentration series of the suspected EDC are combined with radiolabeled forms of the native hormone. Competition for the receptor will yield information about the relative affinity of the EDC compared to the native hormone. Yet, information from binding affinity assays is incomplete, because these assays do not demonstrate if the EDC bound to the hormone receptor will function as an agonist, resulting in hormone action or as an antagonist, actually inhibiting that action. To address these functional questions, endocrinologists have traditionally used in vivo tissue response assays (e.g., prostate growth 20 ), or in vitro...

Dietary estrogens, also known as phytoestrogens, represent a family of plant compounds which are of biological interest because they exhibit both in vivo and in vitro weak estrogenic and anti-estrogenic properties. Phytoestrogens appear to exert their physiological effects through a variety of possible mechanisms, such as their ability to bind to estrogen receptors and their actions on tyrosine kinases and growth factors. Phytoestrogens can be classified into three main categories consisting of isoflavones, lignans, and coumestans. A variety of commonly consumed foods contains appreciable amounts of these plant compounds which have been identified in various human body fluids, such as plasma, urine, bile, saliva, feces, breast milk, prostatic fluid and semen. Accumulating evidence from both clinical and epidemiologi-cal studies has suggested that dietary estrogens may potentially affect the human endocrine system. The existing evidence reviewed here will identify the current research...

Induction of prostatic adenocarcinomas by chemical carcinogens is rare. Only two organic chemical carcinogens, i.e., N-nitroso-bis-(oxopropyl)amine (BOP) and 3,2'-dimethyl-4-aminobiphenyl (DMAB), cause prostate adenocarcinomas upon systemic administration, without any additional concomitant or subsequent treatment 217, 218 . Direct application of chemical carcinogens to prostate tissue in experimental animals produces sarcomas or squamous cell carcinomas (see 5,219 ). Hormonal stimulation of cell proliferation in the prostate at the time of carcinogen administration has been demonstrated to increase the sensitivity of the target cells for tumor induction 199, 220-223 . Dorsolateral prostate adenocarcinomas have been produced at 5-25 incidence when prostatic cell proliferation was stimulated in combination with treatment with indirect-acting carcinogens, such as DMAB and 9,12-dimethylbenz a anthracene, and direct-acting chemical carcinogens, such as N-methyl-N-nitrosourea (MNU) except...

A great loss in binding affinity (Fig. 1). Anti-estrogenic activity of the phytoestrogens could not be detected in this particular study. However, the estrogenic potency of phytoestrogens in this study is significant, especially for ERb, and they may trigger many of the biological responses that are evoked by the physiological estrogens. Interestingly, ERb shows a different anatomical distribution from ERa, being expressed more prominently in tissues such as the brain, ovary, uterus, prostate, lung and urinary tract 72 . ERb is also expressed in breast cells, although apparently weakly 73 . Although there have been many interesting studies on the effects of isoflavones on biochemical targets in tissue culture experiments, the concentrations used by investigators have exceeded 10 M in most cases. Based on simple pharmacokinetic calculations involving daily intakes of isoflavones, absorption from the gut, distribution to peripheral tissues, and excretion, it is unlikely that blood...

Genitalia and the central nervous system (CNS). Other organ systems, like the liver, muscles, and brain, are imprinted as well. The male phenotype arises due to the action of testicular secretions, testosterone, and Mullerian inhibiting substance. Testosterone induces the differentiation of the Wolffian duct system into the epididymis, vas deferens, and seminal vesicles, while its metabolite DHT induces the development of the prostate and male external genitalia. It has been suggested that in the absence of these secretions, the female phenotype is expressed (whether or not an ovary is present). This hypothesis is supported by the observation that when estrogen receptor a and b genes are both knocked out (a ERKO mouse) the female mouse still develops a complete reproductive tract 76 . However, there is some indication of intersex in the ovaries as Sertoli-like cells, normally found in the testis of the male, are found within the ovary. In the CNS, testosterone is aromatized (via the...

Mediated mechanisms have been implicated in the up-regulation of PgR expression in the dysplastic acini of the dorsolateral prostate in response to treatment of testosterone and 17f-estradiol 159 . In the human, ERf has been detected in both normal and cancerous breast tissues or cell lines 153 , and is the predominant ER type in normal breast tissue 158 . Expression of ERf in breast tumors is inversely correlated with the PgR status 157 and variant transcripts of ERf have been observed in some breast tumors 155,156 . ERf and ERa are co-expressed in some breast tumors and a few breast cell lines 153-155 , suggesting an interesting possibility that ERa and ERf proteins may interact with each other and discriminate between target sequences leading to differential responsiveness to estrogens (Fig. 2). In addition, estrogen responses mediated by ERa and ERf may vary with different composition of their co-activators that transmit the effect of ER-ligand complex to the transcription complex...

2 g kg during sex differentiation of the rat or Syrian hamster results in a number of unusual reproductive alterations in male and female progeny 181-184 . In the female rat, oral treatment with 0.2-1 g TCDD kg on GD 15 induced clefting of the phallus with a mild degree of hypospadias in females and a permanent thread of tissue across the opening of the vagina of the progeny 184 . Female progeny treated earlier in gestation with 1 g TCDD kg displayed reduced fecundity, a high incidence of constant estrus, and cystic endometrial hy-perplasia at middle age. Female hamsters, treated by gavage on GD 11 with 2 g TCDD kg, also display clitoral clefting, reduced fertility as a result of several functional reproductive problems, but they did not display the vaginal thread. In TCDD-treated male rat and hamster offspring (dosing as per female offspring above), puberty was delayed, ejaculated and epididymal sperm numbers are reduced, while the reductions in ventral prostate, seminal vesicle, and...

Many studies have demonstrated that prostate cancer is more frequent in men with a family history of prostate cancer by twofold to over tenfold, depending on the number of affected blood relatives as discussed elsewhere 10, 13, 1822 . Although a strong risk factor per se, inherited risk for prostate cancer only explains a small proportion of prostate cancer cases, less than 10 10,18,20 . A range of genetic alterations have been identified in human prostate carcinomas 23 however, few of these have thus far been linked to the heritability of prostate cancer. Susceptibility loci have been identified on chromosome 1 at 1q24-25 (termed HPC1) and at 1q42.2-43 and on the X chromosome at Xq27 -28, which may be involved in hereditary prostate cancer 23-30 . Breast and prostate cancer cluster in some families, which is perhaps related to BRCA1 and BRCA2 mutations in some cases 18,31 . None of these loci have thus far been associated with hormonal factors. A history of venereal disease is a...

Associations between dietary factors and prostate cancer risk have been summarized elsewhere 10,13,17,55-57 . Most studies indicate that a high intake of fat, particularly total fat and saturated fat, is a risk factor for prostate cancer, but the strength of the associations is modest 57 and may be greater in African Americans than European Americans 58 . As much as 25 of prostate cancer in the US may be attributable to a high saturated fat intake 59 . However, Whittemore et al. 22 estimated that dietary fat intake may account for only 10-15 of the difference in prostate cancer occurrence between European Americans and African Americans or Asians. A mechanism of an enhancing effect of fat on prostate carcinogenesis is not understood, but several hypotheses, including hormonal mediation, have been discussed elsewhere 13, 17,57,60 . In addition, a high intake of protein and energy and a low intake of dietary fiber and complex carbohydrates have been found associated with increased risk...

Vasectomy has been identified as a possible risk factor for prostate cancer in seven case-control studies 34, 77-83 and two cohort studies 84, 85 , but no elevation of risk was found in six other case control studies 86-91 and two retrospective cohort studies 92-94 .Although a meta-analysis of 14 studies indicated that there is no causal relation between vasectomy and prostate cancer 95 , further studies will be required to establish definitively whether vasectomy is a true risk factor for prostate cancer 96 - 98 . Three mechanisms by which vasectomy could enhance risk have been proposed elevation of circulating androgens, immunologic mechanisms involving anti-sperm antibodies, and reduction of seminal fluid production 34,77,78,84,89,97,99 . Most studies of pi-tuitary-gonadal function did not find any effect of vasectomy 100-104 , but some studies found changes in hormone levels 89,99,105-109 . There are reports in vasectomized men of slightly elevated circulating testosterone levels...

Several case-control studies have addressed the possibility that sexual factors play a role in prostate cancer etiology (see 13,32-34,111-113 ). In general, the results of these studies suggest that prostate cancer risk may be associated with (1) an early onset of sexual activity, (2) high sexual drive, particularly at young age, (3) a low frequency of intercourse, especially at older age, or (4) a high frequency of intercourse up to 50 years of age and a low frequency thereafter (see 13 ). A positive association has been reported between the level of sexual activity and circulating total testosterone levels in men of 60-79 114 . These findings suggest that a hormonal mechanism may underlie the associations between prostate cancer risk and sexual activity observed in the case-control studies.

Chronic administration of testosterone induces a low to moderate (5-56 ) incidence of prostate cancer in several rat strains 190,194-199 , but not in all strains 200 . The induced tumors were adenocarcinomas in all studies but one, in which also some squamous cell carcinomas were observed 197 , and these carcinomas appeared to develop from the dorsolateral prostate and or coagulating gland, but not the ventral prostate lobe 190,194-198 . The prostate carcinoma incidence in most of these studies was low (5-20 ) 190,194,197,198 . Only the studies reported by Pollard and co-workers using the Lobund Wistar strain sometimes had higher carcinoma incidences, but the incidences varied considerably (0-60 ) 195, 196, 201-204 . In the only other study with the Lobund Wistar strain, a 7 incidence was found 198 . The actual dose of testosterone considerably fluctuated over time in many of these studies from five to ten times control values down to control values 198,200 , but even when the level...

Stimulation of prostatic epithelial cell proliferation by androgens during exposure to chemical carcinogens increases the susceptibility of the rat prostate to cancer induction as a co-carcinogen. Testosterone is a weak complete carcino gen, but is a very strong tumor promotor for the rat prostate at near-physiological plasma concentrations 199 . The very strong tumor-promoting activity of androgens is perhaps responsible for their weak complete carcinogenic activity on the rat prostate. A slight elevation of circulating testosterone can lead to a marked increase in prostate cancer in rat models. This observation is very important in view of the aforementioned weak association between human prostate cancer risk and slightly elevated circulating androgen levels found in some epidemiological studies 173 . Thus, the experimental animal data provide strong support for the concept that minimal increases in circulating an-drogens may have substantial enhancing effects on prostate cancer...

In addition to testicular cancer, increased incidence of tumors in retained Mullerian ducts and other reproductive tract tissues including prostate and seminal vesicle were also seen in the DES animal model. To date, an increased incidence of prostate cancer has not been reported in DES-exposed humans, but it may be due to their young age. Most of the DES-exposed human population is just reaching the fifth decade of life, a time when reproductive tract tumors, for example prostatic lesions, would be expected to increase. Since the mouse model has been predictive of other findings, continued close surveillance of DES-exposed men is warranted.

Cancer is one of the main causes of mortality in the industrialized world, yet the incidence of colon cancer varies worldwide. Bowel cancer is the second most common cancer in the UK, after breast cancer in women and lung cancer in men. Far Eastern populations, such as China and Japan, used to have a much lower incidence 132 .Up to the 1960s, prostate cancer was rare in Japan and Far East countries. The apparent protection of an Asian heritage is speculated to probably be dietary which can be lost upon adoption of a Western style diet 118,133 . Soy is a particular component of Far Eastern diets, not present in the traditional Western diet. There have been several case-control studies examining a role for soybean in protection against colo-rectal cancer, in China, Japan and in Japanese migrants to the US 64 . However, there is not a clear relationship because studies have yielded non-significant results.

For a detailed treatment of this subject the reader is referred to Willis 1 and von Euler and Eliasson 7 , Historically, prostaglandins are the leading compounds of the eicosanoid subfamily of oxylipins. In 1930 Kurzrock and Lieb 8 discovered that seminal fluid exerted pronounced pharmacological effects on uterus preparations. Depending on whether the tissue was obtained from formerly pregnant or from sterile women it responded either by relaxation or by contraction. Analogous results obtained with extracts from the sheep vesicular gland or human seminal fluid were published a few years later by von Euler 9 and Goldblatt 10 . Von Euler characterized the active principle as an unsaturated acidic lipid thus ruling out a hypothesis put forward by others, i.e. that acetylcholine had caused the observed effects. Since the active lipid was also initially found in extracts from the prostate von Euler 11 proposed the name 'prostaglandin'. Only later was it realized that the prostaglandin in...

Prostate were 65 years of age or older. The most common prevalent cancer sites are the breast, prostate, and colon rectum. Figure 1.6 shows the distribution of cancer diagnoses for cancer survivors in 1999. The three common sites mentioned above account for slightly more than 50 of the cancers among survivors. One notes that although lung cancer is the second most common type of cancer among men and women, only 4 of the current survivors have this type of cancer.

It is not yet clearly established that any of the conditions listed above is evoked by, or associated with, endocrine disruption. However, they all have a component of sensitivity towards endocrine-active compounds. For example, tumours of the testis, prostate and female breast are generally sensitive and responsive to sex hormones. In fact, substances that inhibit the action of sex hormones are routinely used in the treatment of these cancers. Moreover, the production of sperm is under the control of sex hormones and may, therefore, be influenced by sex hormone-mimicking compounds. In addition, cryptorchidism and hypospadias are indices of disturbances in gonadal development which may be the result of alterations in sex hormonal function and or metabolism in utero. Indeed, these congenital abnormalities may be biologically associated with testicular cancer and decreased sperm quality. Testicular cancer is more common in patients with cryptorchidism,43,44 and so an increase in the...

Measurement of tissue water diffusion has proven to be remarkably versatile for characterizing tissue structure, as well as tissue changes due to pathology or the effects of therapy. Diffusion MRI has been well studied in the clinical evaluation of ischemic stroke 150 . In oncology, the application of diffusion MRI has focused on the image-based measurement of tumor ADC to detect early changes associated with treatment response 151 . ADC-MRI has been applied with some preliminary success in preclinical and clinical research as an imaging biomarker of treatment response in cancers of the brain 152,153 . head and neck 154 . cervix 155 . breast 156 . and prostate 157 . A related MRI technique, diffusion tensor imaging (DTI), has been used for noninvasive characterization of tissue anisotropy, structural integrity, and connectivity in myocardium 158 and white matter tracts in the brain 159 . In particular, the latter application has been useful in preoperative planning for brain tumor...

In vitro cytotoxicity assays are powerful tools for initial proof of concept and candidate ranking selection. IC50 values (i.e., concentrations required for 50 growth inhibition) are routinely used as an indicator of potency. However, because of the intrinsic simplicity of the system, in vitro assays do not always predict the magnitude of in vivo responses in many cases, they lead to underestimation of the in vivo efficacy for ADCs. In studies developing prostate stem cell antigen (PSCA) ADC for prostate cancer therapy, Ross and colleagues compared in vitro cytotoxicity of maytansinoid-conjugated Abs with their in vivo tumor growth inhibition (141). In vitro cytotoxicity assays in cell lines expressing different levels of PSCA showed that the IC50 values increased as the expression level decreased. In some cases, ADCs showed minimal activity in low-expressing lines. However, significant activity was observed in a xenograft model derived from the same cell lines. Both the duration of...

Only recently, deregulated miRNA expression has been attributed to aberrant HDAC expression in tumors. Noonan et al. have identified a miRNA targeting HDAC1 (miR-449), which induces cell cycle arrest and apoptosis of prostate cancer cells (Noonan et al. 2009). Interestingly, miR-449 is frequently downregulated in prostate cancer. A similar mechanism of regulation has been described for HDAC4

Most prostatic tumors are androgen dependent, and for this reason hormone treatment of prostate cancer is based on the modulation of testosterone to achieve medical castration levels. This can be achieved directly by administration of antiandrogens or indirectly by inhibition of 5a-reductase, the enzyme responsible for the reduction of testosterone to its more active metabolite. Androgen production can also be controlled by inhibition of the release of LH (see Section 7).

The androgenic activity in the prostate is due to 5a-dihydrotestosterone (DHT), since 95 of testosterone entering the prostate is converted to the more potent androgen DHT by the 5a-reductase enzyme of the type 2. Hence, blockade of that enzyme, whose expression is largely restricted to the prostate, facilitates the inhibition of testosterone action on urogenital sinus tissue derivatives, notably

Regarding the nuclear scaffold matrix, one of the seminal findings is its dynamic aspects although a fixed proportion of the total nuclear matrix proteins (NMPs) is always present, a subset of components, among these rare transcription factors, show variations according to the type and differentiation or transformation status of the cell. Here the structure serves to concentrate these proteins via NMTS signals or related principles and to deliver them to the respective S MAR-associated control elements. The relevance of knowing about the identity of these specific NMPs became obvious when Fey and Penman (1988) documented a striking cell type specificity based upon a modified procedure for isolating the nuclear matrix-intermediate filament (NM-IF) portion of the nucleus. Soon thereafter, a correlation with cancer became apparent, explaining the observation that very often the cancer cell nuclei are oddly shaped. Antibodies served to detect cancer-specific NMPs that escape into body...

One of the innovative ways is which researchers have overcome the lack of coverage is to apply the lessons learned from whole- cell Western blots and two-dimensional gels to microarray research. Native protein microarrays are heterogeneous protein pools that have been fractionated using chromatogra-phy. Sartain et al. developed a technique for the separation of native Mycobacterium tuberculosis cytosol and culture filtrate proteins that resulted in 960 unique protein fractions that were used to generate protein microarrays. These 960 fractions represented all the expressed proteins, having some proteins represented in different fractions. When these microarrays were used to profile the reactivity of different disease states, various previously characterized proteins as well as some novel proteins were identified from these fractions using mass spectrometry 10 . A similar approach was utilized in a different field to profile the sera of prostate cancer patients and controls....

A fundamental question which has caused considerable controversy concerns the validity of assuming that the effects of EDs are related to exposure in a linear fashion. It is well known in endocrinology that whilst low concentrations of hormones may induce a tissue response which increases with concentration, hormone concentrations above a certain level often result in an increasingly suppressive effect. Experime'ntal data have indicated just such an inverted-U-shaped dose-response relationship for DES.io2 In this study, prostate weight in 8-month-old male offspring of pregnant mice fed between 0.02 and 200 ug DES kg bodyweight day on gestation days 11-18 increased relative to controls at low doses but decreased at the highest dose. It remains to be seen whether this kind of dose-response relationship is common for other substances with endocrine disrupting activity.

Mitoxantrone is active in breast cancer, acute promyelocitic or myelogenous leukemias, and androgen-independent prostate cancer. Although early reports seemed to indicate that its cardiotoxicity was lower than that of the anthracy-clines,56 this claim has been subsequently challenged.57 Mitoxantrone has been recently approved for treatment of secondary progressive multiple sclerosis (MS).58 The rationale for this application stems from the fact that MS is considered to be an autoimmune disease where a heightened immune action results in the destruction of the myelin of the central nervous system, causing nerve impulses to be slowed or halted and leading to the symptoms of MS. Since chemotherapeutic

Penetratin peptide and showed substantially enhanced uptake into DU145 prostate cancer cells compared to that of unconjugated PNA.72 However, much controversy in this field has centred, in particular, around to what extent improvements in cell uptake afforded by an attached peptide are correlated with steric block biological activities of the PNA within cells.

Cytogenetic abnormalities are frequent in most tumor types and are often associated with tumor characteristics or patient outcome. Altered DNA ploidy (copy number changes) in the cancer genome was described in the 1960s when it was demonstrated that bladder and prostate cancer patients with diploid or tetraploid tumor nuclei had a longer survival rate than patients with triploid or hexaploid tumor nuclei (19).

Phosphatidylinositol-3-kinase protein kinase B (PI3K PKB, Akt) interacts with caveolin and can regulate a number of cellular events, including cell survival. For example, caveolin maintains Akt in an activated state in prostate cancer (Zhuang et al. 2002). Phosphorylation of Akt is thought to occur via interaction of the CSD with, and inhibition of, protein phosphatase 1 and 2A (Li et al. 2003). Caveolin expression can enhance cell death via activation of Akt, for example, sensitizing HepG2 cells to killing by TNF-a (Ono et al. 2004) or arsenite (Shack et al. 2003). Other data indicate that there is a correlation between increased expression of caveolin-1 and Akt activity in colorectal cancer (Kim et al. 2006). In skeletal muscle cells, cell survival can be regulated by a balance between caveolin-3 expression and activation of the PI3K Akt pathway (Smythe and Rando 2006). Interaction of Akt may be recruited by PI3K, which binds to caveolin (Krajewska and Maslowska 2004). Caveolin and...

In the brain, a hypophysectomy can be performed for intractable pain in association with hormonally responsive cancers. The transsphenoidal approach is used for resection or ablation with radiofrequency or alcohol. Both metastatic breast and prostate cancer pain have been treated with very good results. Cingulotomy is usually performed for psychiatric illness, particularly obsessive compulsive disorder and depression, but is also used to treat chronic pain syndromes. Lesioning the cingulate gyrus, part of the limbic system, disrupts the perception of pain. The pain is still felt by the patient, but it does not

Since control of the cell cycle determines if a cell divides or not, there are numerous attempts to influence this process, for instance as a means to stall tumor growth. Recent research has considered many different compounds as regulators of the cell cycle, for instance by targeting cyclin, or inhibition of Cdks. This area of research is vast and rapidly expanding. Here, we shall briefly mention the ability of the natural, sulfur-containing garlic compound diallyl-trisulfide to arrest the cell cycle of certain (cultured) prostate cancer cells at the G2 M transition.

(1) In some cancers decreased apoptosis is the primary cause of tumorous growth, e.g. in follicular B-cell lymphoma and perhaps in early prostate cancer ( &gt 19.1). In these tumors, cells that ought to undergo apoptosis in the course of normal tissue homeostasis survive, which leads to an oversized and progressively disorganized tissue mass. Intrinsic pathway inactivation The most varied assortment of alterations affect the intrinsic apoptotic pathway. BCL2 was discovered as an oncogene protein activated by the most characteristic translocation in follicular lymphoma ( 4.3). It is also over-expressed in a wide range of other cancers, including different types of carcinoma, prominently breast and prostate cancer ( 18.4, 19.2). Alternatively to BCL2, cancers contain high levels of BCL-Xl, which is induced a.o. by the NFkB pathway ( 6.9). Conversely, pro-apoptotic members of the BCL2 family such as BAD or NOXA (Table 7.2) are down-regulated in a variety of cancers, in some cases by...

Human intervention studies of FAP, and of sporadic adenoma development, have shown efficacy associated with NSAID administration, manifested primarily by regression of existing adenomas.38 One report suggests that NSAIDs may be ineffective for primary polyp prevention in FAP patients,39 although this appears discordant with the vast majority of studies that evaluated patients with established polyps. Efficacy appears to exist within all regions of the colorectum, and possibly in other sites as well (esophagus, stomach, prostate, head and neck, pancreas, and breast).

Paraneoplastic vasculitis of the PNS is a rare disorder, characterized by a subacute vasculitic neuropathy, usually presenting as a mononeuropathy multiplex with progressive dysfunction of several nerves, but a symmetrical polyneuropathy has also been observed.56,58 The cases reported are limited in number and most were seen in association with small cell lung cancer and lymphoma, and there were single cases with renal cell, gastric, bile duct, prostate and endometrial cancers.56,58 An anti-Hu antibody association was also noted in a few cases. Its verification with nerve biopsy is crucial, as it may respond to anticancerchemotherapy and immunotherapy for vasculitis.58

Most solid tumors originate from one cell that becomes transformed to become tumorigenic. As the cells divide, the neoplastic growth reaches a critical volume such that free oxygen cannot diffuse far enough to reach the cells ofthe inner mass and they become hypoxic. This critical volume is quite small, only roughly the size of a pinhead, but it is well known that tumors can far surpass this size, thus cancer is able to evade imminent death by hypoxia by the use of HIF-1a and the induction ofblood vessels to the tumor. By producing proangiogenic factors such as VEGF that are crucial in angiogenesis, a tumor provides itself with a means to acquire oxygen and nutrients from the blood. In addition, the accumulation ofblood vessels provides a means of systemic dissemination of tumor cells, also known as metastasis. Interestingly, some breast, prostate and renal carcinomas have an abundance of active HIF-1a even in normoxic conditions 5 . Most renal carcinomas display constitutively...

Interactions between tumor cells and neighboring normal stromal cells are particularly important during metastasis. Setting up stable interactions is crucial for the survival and eventual expansion of metastatic cells. This presupposes a selection for those cancer cells which fit into the target tissue and their successful adaptation to the local environment. For instance, metastatic prostate cancer cells adapt so well to the microenvironment in the bone by interacting with local osteoblasts and osteoclasts that they have been termed 'osteomimetic' ( 19.4). As in normal tissues, these mutual interactions are to a great deal mediated by exchange of paracrine growth factors, and to some extent by direct cell-to-cell interactions. Nakayama M et al (2004) GSTP1 CpG island hypermethylation as a molecular biomarker for prostate

In other studies surface-enhanced laser desorption ionization time-of-flight analysis was applied to microdissected cells because of its sensitivity to smaller amounts of material than other techniques such as 2D gel (42). Using 30,000-50,000 cells of prostate carcinoma specimens, the unique expression of prostate carcinoma-associated protein, called PCa-24 in the epithelial cells, was reached (42). Protein microarrays hold several technical challenges (43). Their application offers the advantage of scalability, flexibility, and automatic processing (43). Arrays may also enable the control of key parameters such as temperature, pH, and cofactor concentration, which are not easily afforded by cell-based systems.

We illustrate the statistical approach based on the individual-level and trial-level associations using two trials in patients with advanced (metastatic) prostate cancer. These trials compared oral liarozole, an experimental retinoic acid metabolism-blocking agent developed by the Janssen Research Foundation, with two antiandrogenic drugs cyproterone acetate (CPA) in the first trial and flutamide in the second. In both trials, patients were in relapse after first-line endocrine therapy 23 . The trials accrued 312 and 284 patients, respectively. Each trial was multinational and multicentric. Since our analyses require the estimation of the effect of treatment in multiple trials or other meaningful groups of patients, we grouped the patients by trial and by country. This allowed us to define 19 groups containing between four and 69 patients per group. The primary endpoint of the trials was overall survival from the start of treatment. Assessments were undertaken before the start of...

Figure 2 (a) The survival of patients with a PSA response differs substantially from that of patients without a PSA response. At any point in time the odds of surviving beyond that time are more than five times higher for patients with a PSA response as compared to patients without such a response (see text). (b) The treatment effects on survival and on PSA response show no correlation in advanced prostate cancer (R 0.05). Each circle shows treatment effects estimated in one of the countries in which the trials were conducted. (The size of the circle is proportional to the number of patients.) Figure 2 (a) The survival of patients with a PSA response differs substantially from that of patients without a PSA response. At any point in time the odds of surviving beyond that time are more than five times higher for patients with a PSA response as compared to patients without such a response (see text). (b) The treatment effects on survival and on PSA response show no correlation in...

506 started in 1994, and it has shown a particular good activity in ovarian and breast cancer. The related hydroxy derivative J-107088 is more active in vitro than NB-506 or CPT in the induction of topoisomerase I cleavage complexes.107 This compound is being studied clinically and has shown potent activity against lung and prostate cancers, and a wider therapeutic window than many established drugs.108 Its glycoside edotecarin has shown activity in clinical trials for colon, breast, and other cancers. The larger size of the imide nitrogen substituent hampers imide ring opening and glucuronidation and leads to an increased half-life.